title: Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation.
abstract: OBJECTIVE
  Intracellular amyloid β-protein (Aβ) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied.
  
  
  METHODS
  The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL) /PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aβ degradation, activity of Aβ-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells.
  
  
  RESULTS
  After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aβ, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells.
  
  
  CONCLUSIONS
  3xTg-AD mice show intraneuronal Aβ accumulation and memory disturbances before extracellular Aβ deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aβ and p-tau levels by APO treatment strongly suggest that intraneuronal Aβ is an important therapeutic target and APO will be a novel drug for AD.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Himeno
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.forename: Linqing
authors.initials: L
authors.lastname: Ma
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nakamura
authors.forename: Katsue
authors.initials: K
authors.lastname: Miyoshi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Sakae
authors.forename: Kyoko
authors.initials: K
authors.lastname: Motomura
authors.forename: Naoko
authors.initials: N
authors.lastname: Soejima
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamasaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tabira
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007339:Insulysin / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018709:Statistics, Nonparametric; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018491:Dopamine Agonists; D016875:tau Proteins; D015260:Neprilysin; D007339:Insulysin; D046988:Proteasome Endopeptidase Complex; D001058:Apomorphine